Abstract
ObjectiveThe first objective was to investigate if intracellular and extracellular levels of reactive oxygen species (ROS) within the mouse aorta increase before or after diet-induced lesion formation. The second objective was to investigate if intracellular and extracellular ROS correlates to cell composition in atherosclerotic lesions. The third objective was to investigate if intracellular and extracellular ROS levels within established atherosclerotic lesions can be reduced by lipid lowering by diet or atorvastatin.Approach and ResultsTo address our objectives, we established a new imaging technique to visualize and quantify intracellular and extracellular ROS levels within intact mouse aortas ex vivo. Using this technique, we found that intracellular, but not extracellular, ROS levels increased prior to lesion formation in mouse aortas. Both intracellular and extracellular ROS levels were increased in advanced lesions. Intracellular ROS correlated with lesion content of macrophages. Extracellular ROS correlated with lesion content of smooth muscle cells. The high levels of ROS in advanced lesions were reduced by 5 days high dose atorvastatin treatment but not by lipid lowering by diet. Atorvastatin treatment did not affect lesion inflammation (aortic arch mRNA levels of CXCL 1, ICAM-1, MCP-1, TNF-α, VCAM, IL-6, and IL-1β) or cellular composition (smooth muscle cell, macrophage, and T-cell content).ConclusionsAortic levels of intracellular ROS increase prior to lesion formation and may be important in initiation of atherosclerosis. Our results suggest that within lesions, macrophages produce mainly intracellular ROS whereas smooth muscle cells produce extracellular ROS. Short term atorvastatin treatment, but not lipid lowering by diet, decreases ROS levels within established advanced lesions; this may help explain the lesion stabilizing and anti-inflammatory effects of long term statin treatment.
Highlights
Reactive oxygen species (ROS) are highly reactive molecules continuously produced by mitochondrial electron transport and by enzymes such as NADPH-oxidases, xanthine oxidases and lipoxygenases [1,2,3]
We found that intracellular, but not extracellular, ROS levels increased prior to lesion formation in mouse aortas
Both intracellular and extracellular ROS levels were increased in advanced lesions
Summary
Reactive oxygen species (ROS) are highly reactive molecules continuously produced by mitochondrial electron transport and by enzymes such as NADPH-oxidases, xanthine oxidases and lipoxygenases [1,2,3]. Excessive ROS levels irreversibly damage proteins, lipids, carbohydrates, and DNA [3, 4]. High ROS levels are considered to promote atherosclerosis progression, and possibly initiation. There is no non-invasive technique that allows arterial ROS to be determined in vivo. Available techniques to assess arterial ROS do not discriminate between intracellular and extracellular ROS [7]. Such discrimination is important because intracellular and extracellular ROS promote atherosclerosis development through different mechanisms. Excessive levels of intracellular ROS damage DNA, proteins, lipids and carbohydrates inside cells whereas extracellular ROS oxidize lipoproteins and activate collagen-degrading matrix metalloproteinases outside cells [1, 3]
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